Biology subjects

Eilers, M.

Publications and source records attributed to Eilers, M..

18 recordsLinked to original sources

bioRxiv2026

Replication-coupled chromatin assembly cooperates with ATR/CHK1 signaling to suppress DNA damage and premature MMB-dependent mitotic transcription

Faithful genome duplication requires coordination of DNA replication, chromatin assembly, and checkpoint signaling to prevent inappropriate mitotic progression. Using a targeted siRNA screen for factors modulating CHK1 inhibitor-induced DNA damage and premature mitotic entry, we identified replication-coupled chromatin assembly as a determinant of checkpoint dependence. Acute depletion of the CAF-1 subunit CHAF1A modestly delayed S-phase progression but caused little DNA damage, whereas inhibition of CHK1 or ATR triggered extensive DNA damage, premature mitotic entry, and loss of viability. Transcriptomic analyses revealed that CHK1 inhibition induced a transcriptional response enriched for B-MYB/Myb-MuvB (MMB) target genes in CHAF1A-deficient cells. Notably, induction of these genes occurred without corresponding increases in promoter accessibility, suggesting that enhanced MMB-dependent transcription is largely independent of widespread promoter opening. B-MYB depletion attenuated MMB target-gene induction, premature mitotic entry, and DNA damage. Depletion of ASF1 and NAP1L1 similarly enhanced checkpoint inhibitor sensitivity, indicating that increased dependence on ATR-CHK1 signaling is a broader consequence of impaired histone chaperone function. Together, our findings establish a functional link between replication-coupled chromatin assembly, ATR-CHK1 signaling, and MMB-dependent mitotic transcription.

molecular biology↗

bioRxiv2026

Pharmacological arginine deprivation renders pancreatic cancer cells susceptible to senolysis and inhibition of the integrated stress response

Pancreatic ductal adenocarcinoma (PDAC) is almost inevitably fatal and largely resistant to current chemotherapy regimens. Senolysis, i. e. the selective elimination of senescent cells, and the targeting of cancer specific cellular metabolism are two novel treatment approaches that have proven to be effective for a variety of cancer types in pre-clinical studies. We now demonstrate that pharmacological depletion of arginine with pegylated recombinant human arginase 1 (PEG-rhARG1) induced senescence and activated the integrated stress response (IRS) in PDAC cells. Cells treated in such a manner were strikingly susceptible towards senolysis with ABT-263 (navitoclax) and also sensitive towards inhibition of the IRS. These results demonstrate a novel mechanism for an induced sensitivity of PDAC cells that could be exploited for cancer therapy.

cancer biology↗

bioRxiv2026

MYC/MIZ1 suppression of lysosomal protein degradation drives immune evasion in pancreatic ductal adenocarcinoma

The MYC oncoprotein promotes immune evasion of pancreatic ductal adenocarcinoma (PDAC), but the underlying molecular mechanisms are not fully understood. Here we show that MYC protects PDAC tumors from CD4+ T cell-dependent elimination. Single cell sequencing shows that MYC suppression in tumor cells increases amino acid availability and broadly activates amino acid-responsive gene expression programs in immune cell populations. This occurs because MYC-driven uptake depletes free amino acids from tumor interstitial fluid and plasma, while MYC compromises macropinocytosis and autophagy, both of which depend on lysosomal protein degradation. MYC engages the POZ/BTB transcription factor MIZ1 to suppress lysosomal genes regulated by the TFE3/TFEB/MITF network or by free MIZ1, thereby inhibiting lysosomal protein degradation. An orthogonal genetic model enabling transient, selective inhibition of amino acid uptake in tumor cells recapitulates the effects of MYC depletion on amino acid levels in the tumor microenvironment and induces complete, CD4+ T cell-dependent tumor eradication with long-term survival. We propose that MYC-mediated, cell-autonomous disruption of lysosome function coupled to non-cell-autonomous protection from immune clearance allows MYC-low cells to benefit from MYC-high neighbors, such that intratumoral heterogeneity in MYC expression confers a selective advantage to the entire tumor. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/740267v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@140d2ccorg.highwire.dtl.DTLVardef@cf5f1borg.highwire.dtl.DTLVardef@6d132aorg.highwire.dtl.DTLVardef@10535e6_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Tafazzin-Mediated Cardiolipin Remodeling Controls Metabolic Stress Response and Effector Function of Inflammatory T Cells

Clonal expansion and effector differentiation of T cells require extensive metabolic reprogramming. This includes the restructuring of the inner mitochondrial membrane (IMM) to enhance respiration by increasing chemiosmotic coupling efficiency. Cardiolipin, a unique phospholipid that is exclusively synthesized and localized in the IMM, modulates the biophysical properties of the electron transport chain (ETC) in tissues with high energy demands, such as cardiomyocytes and skeletal muscle. However, it remains unclear whether cardiolipin is also important for metabolic remodeling during T helper (Th) cell differentiation. In this study, we show that cardiolipin transacylation, catalyzed by the enzyme Tafazzin, supports the clonal expansion and effector function of inflammatory Th1 and Th17 cells in vitro and in models of autoimmune colitis and encephalomyelitis. At the molecular level, we demonstrate that loss of Tafazzin-mediated cardiolipin maturation induces a metabolic and transcriptional stress response in Th cells to compensate for impaired coupling efficiency of the ETC complexes and disrupted cellular redox homeostasis. However, the genetic program that restores cellular homeostasis and mitigates oxidative stress concurrently impairs the effector functions of inflammatory T cells, such as cytokine production. Our findings also provide insights into the complex clinical manifestation of patients with Barth syndrome (BTHS) caused by mutations in the human TAFAZZIN gene. BTHS is characterized by cardiac and skeletal myopathy as well as neutropenia and an increased susceptibility to infections. Although the molecular basis of the immunodeficiency remains poorly understood, our findings suggest that impaired Th cell function contributes to the immunopathology observed in BTHS patients.

immunology↗

bioRxiv2025

Riboflavin metabolism shapes FSP1-driven ferroptosis resistance

Membrane protection against oxidative insults is achieved by the concerted action of glutathione peroxidase 4 (GPX4) and endogenous lipophilic antioxidants such as ubiquinone and vitamin E. Deficiencies in these protective systems lead to an increased propensity to phospholipid peroxidation and ferroptosis. More recently, ferroptosis suppressor protein 1 (FSP1) was identified as a critical ferroptosis inhibitor acting via regeneration of membrane-embedded antioxidants. Yet, regulators of FSP1 are largely uncharacterised, and their identification is essential for understanding the mechanisms buffering phospholipid peroxidation and ferroptosis. Here, we conducted a focused CRISPR-Cas9 screen to uncover factors influencing FSP1 function, identifying riboflavin (vitamin B2) as a new modulator of ferroptosis sensitivity. We demonstrate that riboflavin, unlike other vitamins that act as radical-trapping antioxidants, supports FSP1 stability and the recycling of lipid-soluble antioxidants, thereby mitigating phospholipid peroxidation. Furthermore, we show that the riboflavin antimetabolite roseoflavin markedly impairs FSP1 function and sensitises cancer cells to ferroptosis. Thus, we uncover a direct and actionable role for riboflavin in maintaining membrane integrity by promoting membrane tolerance to lipid peroxidation. Our findings provide a rational strategy to modulate the FSP1-antioxidant recycling pathway and underscore the therapeutic potential of targeting riboflavin metabolism, with implications for understanding the interaction of nutrients and their contributions to a cells antioxidant capacity.

cell biology↗

bioRxiv2025

The MYCN/Aurora-A complex is a cyclin activating kinase for CDK12

Deregulated MYCN is a driver of aggressive pediatric and adult neuroendocrine tumors, but critical oncogenic processes downstream of MYCN remain poorly defined. In neuroblastoma, MYCN interacts with and activates the Aurora-A kinase. Here we show that Aurora-A is a CDK-activating kinase for CDK12 by phosphorylating T893 in the T-loop, thereby enhancing its kinase activity. Aurora-A-dependent activation of CDK12 controls phosphorylation of T4 of RNA polymerase and recruits transcription termination complexes, thereby preventing transcription-replication conflicts. Enhanced crosslinking and immunoprecipitation sequencing reveals that Aurora-A associates with splice sites on nascent RNA. RNA-bound Aurora-A is catalytically inactive. MYCN competes with RNA for binding to Aurora-A and displaces Aurora-A from RNA in cells, promoting its CDK12 kinase activity. Combining Aurora-A and CDK12 inhibition potently suppresses the growth of MYCN-amplified neuroblastoma cells and patient-derived xenografts. Our data demonstrate that an Aurora-A/CDK12-dependent transcription termination pathway is a critical and targetable dependency of MYCN-driven tumors.

cancer biology↗

bioRxiv2024

RNA-mediated MYC multimerization suppresses innate immune signaling

In response to perturbed transcription elongation, the MYC oncoprotein multimerizes and undergoes a phase transition; the underlying mechanisms and their function are unknown. Here, we show that MYC re-localizes from its canonical location on DNA to RNA in response to the accumulation of intronic RNA. MYC binds RNA directly, which enhances its multimerization. MYC multimers concentrate the nuclear exosome, a 3-5 RNA exonuclease, and its targeting complexes around double-stranded RNA and R-loops, and promote exosome recruitment to R-loops. RNA binding of MYC suppresses activation of the innate immune kinase TBK1. Upon MYC depletion, intron-derived dsRNAs, including RNA derived from repetitive elements and small nucleolar RNAs, accumulate on TLR3, a pattern recognition receptor that activates TBK1. In MYC-depleted cells, TLR3-bound snoRNAs carry aberrant 3-ends, indicating defective exosomal processing. Our data show that the phase transition of MYC is a RNA-driven stress response that suppresses the accumulation of immunogenic RNAs.

molecular biology↗

bioRxiv2024

A trimeric USP11/USP7/TCEAL1 complex stabilizes RNAPII during early transcription to sustain oncogenic gene expression

During early transcription, RNA polymerase II (RNAPII) undergoes a series of structural transitions controlled by cyclin-dependent kinases. Whether protein ubiquitylation and proteasomal degradation affect the fate of RNAPII close to promoters is less well understood. Here we show that the deubiquitylating enzyme USP11 and its heterodimeric partner USP7 form a trimeric complex with TCEAL1, a member of the poorly understood TCEAL (TCEA/TFIIS-like) protein family. TCEAL1 shares sequence homology with the RNAPII interaction domain of the TCEA/TFIIS elongation factor, which controls the fate of backtracked RNAPII. TCEAL1 stabilizes complexes of USP11 with USP7 and with RNAPII. TCEAL1 is recruited to core promoters when transcription elongation is blocked and globally enhances the chromatin association of RNAPII during early transcription. Mechanistically, the USP11/USP7/TCEAL1 complex competes with TFIIS for binding to core promoters and protects RPB8, an essential subunit of RNAPII, from degradation, likely preventing excessive TFIIS-mediated transcript cleavage and RNAPII disassembly. In neuroblastoma and other tumors, TCEAL1-dependent genes define a TGF beta-dependent gene expression program that is characteristic for mesenchymal and invasive tumor cell types, suggesting that the USP11/USP7/TCEAL1 trimer stabilizes RNAPII during early transcription to support a critical oncogenic gene expression program (190 words).

cancer biology↗

bioRxiv2024

NEAT1 promotes genome stability via m6A methylation-dependent regulation of CHD4

Long non-coding (lnc)RNA emerge as regulators of genome stability. The nuclear enriched abundant transcript 1 (NEAT1) locus encodes two lncRNA isoforms that modulate gene expression, growth and proliferation in mammals. Interestingly, NEAT1 transcripts are overexpressed in many tumours and induced by DNA damage, suggesting a genome-protective function. However, the precise role of NEAT1 in the DNA damage response (DDR) is unclear. Here, we investigate the expression, modification levels, localization and structure of NEAT1 in response to DNA double-strand breaks (DSBs) induced by the topoisomerase-II inhibitor etoposide or the locus-specific endonuclease AsiSI. We find that induction of DSBs increases both the levels and N6-methyladenosine (m6A) marks on NEAT1, which promotes alterations in NEAT1 secondary structure and accumulation of hyper-methylated NEAT1 at a subset of promoter-associated DSBs to facilitate efficient DSB signalling. The depletion of NEAT1, in turn, delays the response to DSBs and triggers elevated DNA damage. The genome-protective role of NEAT1 is mediated by the RNA methyltransferase 3 (METTL3) and involves spreading of the chromodomain helicase DNA binding protein 4 (CHD4) upon release from NEAT1. Together, we describe a novel RNA-dependent DDR pathway that couples NEAT1 to the recognition and repair of DSBs.

molecular biology↗

bioRxiv2024

Targeting MYCN upregulates L1CAM tumor antigen in MYCN-dysregulated neuroblastoma to increase CAR T cell efficacy

BackgroundCurrent treatment protocols have only limited success in pediatric patients with neuroblastomas harboring amplifications of the central oncogene, MYCN. Adoptive T cell therapy presents an innovative strategy to improve cure rates. However, L1CAM-targeting CAR T cells achieved only limited response against refractory/relapsed neuroblastoma in an ongoing phase I trial to date. Here, we investigate how oncogenic MYCN levels influence tumor cell response to CAR T cells, as one possible factor limiting success in trials. MethodsHigh MYCN levels were induced in SK-N-AS cells harboring the normal diploid MYCN complement using a tetracycline-inducible system. The inducible MYCN cell model or MYCN-amplified neuroblastoma cell lines were cocultured with L1CAM-CAR T cells. CAR T cell effector function was assessed via activation marker expression (flow cytometry), cytokine release and tumor cytotoxicity (biophotonic signal assessment). The cell model was characterized using RNA sequencing, and our data compared to publicly available RNA and proteomic data sets from neuroblastomas. ChIP-sequencing data was used to determine transcriptional L1CAM regulation by MYCN using public data sets. Synergism between CAR T cells and the MLN8237 AURKA inhibitor, which indirectly inhibits MYCN activity, was assessed in vitro using the Bliss model and in vivo in an immunocompromised mouse model. ResultsInducing high MYCN levels in the neuroblastoma cell model reduced L1CAM expression and, consequently, L1CAM-CAR T cell effector function (activation, cytokine release and cytotoxicity) in vitro. Primary neuroblastomas possessing high MYCN levels expressed lower levels of both the L1CAM transcript and L1CAM tumor antigen. Indirectly inhibiting MYCN via AURKA using MLN8237 treatment restored L1CAM expression on tumor cells in vitro and restored L1CAM-CAR T cell effector function. Combining MLN8237 and L1CAM-CAR T cell treatment synergistically increased neuroblastoma-directed killing in MYCN-overexpressing cells in vitro and in vivo concomitant with severe in vivo toxicity. ConclusionWe shed new light on a primary resistance mechanism in MYCN-driven neuroblastoma against L1CAM-CAR T cells via target antigen downregulation. These data suggest that combining L1CAM-CAR T cell therapy with pharmacological MYCN inhibition may benefit patients with high-risk neuroblastomas harboring MYCN amplifications.

immunology↗

bioRxiv2023

Association with TFIIIC limits MYCN localization in hubs of active promoters and chromatin accumulation of non-phosphorylated RNA Polymerase II

MYC family oncoproteins regulate the expression of a large number of genes and broadly stimulate elongation by RNA polymerase II. While the factors that control the chromatin association of MYC proteins are well understood, much less is known about how interacting proteins mediate MYCs effects on transcription. Here we show that TFIIIC, an architectural protein complex that controls the three-dimensional chromatin organization at its target sites, binds directly to the amino-terminal transcriptional regulatory domain of MYCN. Surprisingly, TFIIIC has no discernible role in MYCN-dependent gene expression and transcription elongation. Instead, MYCN and TFIIIC preferentially bind to promoters with paused RNAPII and globally limit the accumulation of non-phosphorylated RNAPII at promoters. Consistent with its ubiquitous role in transcription, MYCN broadly participates in hubs of active promoters. Depletion of TFIIIC further increases MYCN localization to these hubs. This increase correlates with a failure of the nuclear exosome and BRCA1, both of which are involved in nascent RNA degradation, to localize to active promoters. Our data suggest that MYCN and TFIIIC exert an censoring function in early transcription that limits promoter accumulation of inactive RNAPII and facilitates promoter-proximal degradation of nascent RNA.

molecular biology↗

bioRxiv2023

Direct RNA-binding by MYCN mediates feedback from RNA processing to transcription control

The MYCN oncoprotein broadly binds active promoters in a heterodimer with its partner protein MAX. MYCN also interacts with the nuclear exosome, a 3-5 exoribonuclease complex, suggesting a function in RNA metabolism. Here we show that MYCN forms stable high molecular weight complexes with the exosome and multiple RNA-binding proteins. In cells, MYCN binds to thousands of intronic RNAs; recombinant MYCN directly binds RNA via a short, highly conserved sequence termed MYCBoxI. Perturbing exosome function results in global re-localization of MYCN from promoters to intronic RNAs. At promoters, MYCN is then replaced by the MNT(MXD6) repressor protein, which inhibits MYCN-dependent transcription. MYCN promotes the degradation of its bound introns via the nuclear exosome targeting (NEXT) complex. Our data demonstrate that MYCN is an RNA-binding protein that regulates nascent transcript turnover and show that competition between its RNA- and DNA-bound states links the dynamics of the MYCN/MAX/MXD network to mRNA processing.

cancer biology↗

bioRxiv2023

Regulation of BCR-mediated Ca2+ mobilization by MIZ1-TIMBIM4 safeguards IgG1+ GC B cell positive selection

The transition from IgM to affinity-matured IgG antibodies is vital for effective humoral immunity. This is facilitated by germinal centers (GCs) through affinity maturation and preferential accumulation of IgG+ B cells over IgM+ B cells. However, it is not known whether the positive selection of the different immunoglobulin isotypes within GCs varies in its dependency on specific transcriptional mechanisms. Here, we identified IgG1+ GC B cell transcription factor dependency using CRISPR-Cas9 and conditional mouse genetics. We found that MIZ1 was specifically required for IgG1+ GC B cell survival during positive selection, whereas IgM+ GC B cells were largely independent. Mechanistically, MIZ1 induced TMBIM4, an ancestral anti-apoptotic protein that regulated inositol trisphosphate receptor mediated Ca2+ mobilization downstream of IgG1. The MIZ1-TMBIM4 axis prevented mitochondrial dysfunction-induced IgG1+ GC cell death caused by excessive Ca2+ accumulation. This study uncovers a unique immunoglobulin isotype-specific dependency, on a hitherto unidentified mechanism in GC positive selection.

immunology↗

bioRxiv2023

Stabilisation of β-Catenin-WNT signalling by USP10 in APC-truncated colorectal cancer drives cancer stemness and enables super-competitor signalling

The contribution of deubiquitylating enzymes to {beta}-Catenin stabilisation in intestinal stem cells and colorectal cancer (CRC) is poorly understood. Here, we report the deubiquitylase USP10 as an APC-truncation- specific enhancer of {beta}-Catenin stability, potentiating WNT signalling in CRC and cancer stem cells. Mechanistically, interaction studies in various CRC cell lines and in vitro binding studies, together with computational modelling, revealed that USP10 binding to {beta}-Catenin is mediated via the unstructured N-terminus of USP10 and requires the absence of full-length APC. Notably, loss of USP10 in CRISPR engineered intestinal organoids reduces tumorigenic properties of CRC and blocks the super competitor-signalling of APC-mutated CRC. Furthermore, reduction of USP10 induces the expression of differentiation genes, and opposes the APC-truncated phenotype in an intestinal hyperplasia model of D.melanogaster. Taken together, our findings reveal USP10s role in intestinal tumourigenesis by stabilising {beta}-Catenin, leading to aberrant WNT signalling, enhancing cancer cell stemness and implicate the DUB USP10 as a cancer specific therapeutic vulnerability in Apc truncated CRC.

cancer biology↗

bioRxiv2022

Selenocysteine metabolism is a targetable vulnerability in MYCN-amplified cancers

Understanding the operational molecular, and metabolic networks that determine the balance between pro- and anti-ferroptotic regulatory pathways could unravel unique vulnerabilities to be exploited for cancer therapy. Here we identify the selenoprotein P (SELENOP) receptor, LRP8, as a key determinant protecting MYCN-amplified neuroblastoma cells from ferroptosis in vitro and in orthotopic neuroblastoma mouse models. Specifically, the exquisite dependency on LRP8-mediated selenocysteine import is caused by the failure of MYCN-amplified cells to efficiently utilize alternative forms of selenium/selenocysteine based uptake necessary for selenoprotein biosynthesis. Increased activity of one of such transporters, SLC7A11, in MYCN-amplified cells leads to cysteine overload, progressive mitochondrial decline and impaired proliferation. These data reveal in LRP8 a targetable, and specific vulnerability of MYCN-amplified neuroblastoma cells and disclose a yet-unaccounted mechanism for selective ferroptosis induction that has the potential to become an important therapeutic entry point for MYCN-amplified neuroblastoma. Statement of significanceGiven the largely unsuccessful repurposing of adult oncology drugs for the treatment of neuroblastoma, our discoveries pave the way for novel ferroptosis based strategies for this entity. Specifically, targeting of LRP8 may offer novel therapeutic and safer opportunities for a number of pediatric malignancies and MYCN driven cancers.

cancer biology↗

bioRxiv2021

Design, Synthesis and Evaluation of WD-repeat containing protein 5 (WDR5) degraders

Histone H3K4 methylation serves as post-translational hallmark of actively transcribed genes and is introduced by histone methyltransferases (HMT) and its regulatory scaffolding proteins. One of these is the WD-repeat containing protein 5 (WDR5) that has also been associated with controlling long non-coding RNAs and transcription factors including MYC. The wide influence of dysfunctional HMTs complexes and the typically upregulated MYC levels in diverse tumor types suggested WDR5 as an attractive drug target. Indeed, protein-protein interface inhibitors for two protein interaction interfaces on WDR5 have been developed. While such compounds only inhibit a subset of WDR5 interactions, chemically induced proteasomal degradation of WDR5 might represent an elegant way to target all oncogenic function. This study presents the design, synthesis and evaluation of two diverse WDR5 degrader series based on two WIN site binding scaffolds and shows that linker nature and length strongly influence degradation efficacy.

cancer biology↗

bioRxiv2019

The USP28-{triangleup}Np63 axis is a vulnerability of squamous tumours

The transcription factor {Delta}Np63 is a master regulator that establishes epithelial cell identity and is essential for the survival of SCC of lung, head and neck, oesophagus, cervix and skin. Here, we report that the deubiquitylase USP28 stabilizes {Delta}Np63 protein and maintains elevated {Delta}NP63 levels in SCC by counteracting its proteasome-mediated degradation. Interference with USP28 activity by genetic means abolishes the transcriptional identity of SCC cells and suppresses growth and survival of human SCC cells. CRISPR/Cas9-engineered mouse models establish that both induction and maintenance of lung SCC strictly depend on endogenous USP28. Targeting {Delta}Np63 protein abundance in SCC via inhibition of USP28 therefore is a feasible strategy for the treatment of SCC tumours.\n\nSignificanceSCC depend on {Delta}Np63, and its protein abundance is tightly controlled by the ubiquitin proteasome system. Here, we demonstrate the dependence of SCC on USP28 for various human SCC in vitro and in vivo using murine lung tumour models. As inhibitors for deubiquitylases become available, targeting USP28 is a promising therapeutic strategy.

cancer biology↗

bioRxiv2019

Control of MYC-dependent apoptotic threshold by a co-amplified ubiquitin E3 ligase UBR5

MYC protein expression has to be tightly controlled to allow for maximal cell proliferation without inducing apoptosis. Here we discover UBR5 as a novel MYC ubiquitin ligase and demonstrate how it functions as a molecular rheostat to prevent excess accumulation of MYC protein. UBR5 effects on MYC protein stability are independent on N-terminal FBW7 degron of MYC. Endogenous UBR5 inhibition induces MYC protein expression and activates MYC target genes. Moreover, UBR5 governs MYC-dependent phenotypes in vivo in Drosophila. In cancer cells, UBR5-mediated MYC protein suppression diminishes cell killing activity of cancer therapeutics. Further, we demonstrate that UBR5 dominates MYC protein expression at the single-cell level in human basal-type breast cancer tissue. Myc and Ubr5 are co-amplified in MYC-driven human cancer types, and UBR5 controls MYC-mediated apoptotic threshold in co-amplified basal type breast cancer cells. In summary, UBR5 is a novel MYC ubiquitin ligase and an endogenous rheostat for MYC protein expression in vivo. Clinically, expression of UBR5 may be important for protection of breast cancer cells from drug-induced, and MYC-dependent, apoptosis.

cancer biology↗